tbuckley/cabot-search huggingface dataset:
Abstract 1874: Use of high throughput SPR to characterize antibodies to common cancer biomarkers
Authors: Sergei Bibikov, John Rosenfeld, Kevin J. Harvey
Journal: Cancer Research (2022)

Abstract As a disease of mis-regulation, cancer is characterized both genetically and proteomically, requiring high quality tools to dissect the change difference between cell states. Among the reagents used to characterize biological systems at the protein level, antibodies are routinely applied, and engineered versions have proven useful for treating multiple therapeutic indications. We have generated a human proteome wide toolbox of polyclonal antibodies, identifying three antigenic 14mer sequences within each of the 20,000+ open reading frames at N-terminal, middle and C-terminal regions. Using a high throughput SPR system, Carterra LSA, we are able to define average on-rates, off-rates, and KD’s for pAb’s generated to important cancer regulators and biomarkers, including KRAS, STAT3, and Gli1. Due to the small size of the peptide targets, the kinetics of the observed interactions with polyclonal antibodies exhibit remarkable 1:1 fit typically observed when measuring monoclonal antibody affinities. The platform is a sensitive system capable of both identifying multiple antibody-antigen interactions with KD in the nanomolar to picomolar range, but also as a mass screening tool for developing de novo antibody pairs. We define the kinetic characteristics of these antibody reagents relative to performance in western blotting specifically. Improving the characterization of such widely used tools is critical for advancing translational opportunities into use in the clinic. Citation Format: Sergei Bibikov, John Rosenfeld, Kevin J. Harvey. Use of high throughput SPR to characterize antibodies to common cancer biomarkers [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 1874.
Abstract 2942: Robust sample recovery post-digital PCR for downstream genomic applications
Authors: Kimberley Gutierrez, Benjamin Foret, Cécile Jovelet, Allison C. Mallory
Journal: Cancer Research (2022)

Abstract Droplet microfluidics technologies, and particularly, digital PCR have provided highly precise and sensitive detection of genetic targets. There is a strong interest for researchers to reuse sample due to sample scarcity, as well as, to further characterize or validate their experimental findings. Historically, recovery of PCR products for downstream genomic testing applications has been challenging due to the stability of the sample post-reaction. Stilla Technologies has developed Crystal Digital PCR™ and the naica® system, a flexible and highplex droplet and imaging-based digital PCR platform that allows for multi-color detection of genetic targets with the ability to also recover samples after the reaction is performed. This study shows how the 6-color naica digital PCR system workflow can be combined with a simple protocol for sample recovery. DNA contained in the recovered emulsion is extracted using a standard chloroform protocol that takes approximately 1 hour. DNA recovery rate assessment showed high percentage recovery of droplet sample and on average, 70% of the total DNA present from the initial sample recovered. Recovered DNA from the droplet crystal was sequenced and the results were confirmed by qPCR. The droplet and sample recovery protocol post-digital PCR has potential applications to support validation of Crystal Digital PCR results, concordance alongside a multitude of genomic platforms, and further characterization of biomarkers and mutations with profiling platforms such as NGS. Citation Format: Kimberley Gutierrez, Benjamin Foret, Cécile Jovelet, Allison C. Mallory. Robust sample recovery post-digital PCR for downstream genomic applications [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 2942.
Targeting Lysine-Specific Demethylase 1 Rescues Major Histocompatibility Complex Class I Antigen Presentation and Overcomes Programmed Death-Ligand 1 Blockade Resistance in SCLC
Authors: Evelyn M Nguyen, Hirokazu Taniguchi, Joseph M Chan, Yingqian A Zhan, Xiaoping Chen, Juan Qiu, Elisa de Stanchina, Viola Allaj, Nisargbhai S Shah, Fathema Uddin, Parvathy Manoj, Michael Liu, Sheng F Cai, Ross Levine, Álvaro Quintanal-Villalonga, Triparna Sen, Andrew Chow, Charles M Rudin
Journal: Journal of Thoracic Oncology (2022)
Analysis of Neuropsychiatric Diagnoses After Montelukast Initiation
Authors: Tapio Paljarvi, Julian Forton, Sierra Luciano, Kimmo Herttua, Seena Fazel
Journal: JAMA Network Open (2022)

<h3>Importance</h3> The evidence base for the association between montelukast and adverse neuropsychiatric outcomes is mixed and inconclusive. Several methodological limitations have been identified in the evidence base on the safety of montelukast in observational studies. <h3>Objective</h3> To investigate the association between new montelukast exposure and 1-year incident neuropsychiatric diagnoses with improved precision and control for baseline confounders. <h3>Design, Setting, and Participants</h3> This propensity score–matched cohort study was conducted using electronic health records from 2015 to 2019 in the TriNetX Analytics Network patient repository of more than 51 million patients from 56 health care organizations, mainly in the US. Included patients were those aged 15 to 64 years at index prescription for montelukast or for control prescription who had a history of asthma or allergic rhinitis. After propensity score matching for various baseline confounders, including comorbidities and dispensed prescription medicines, we included 154 946 patients, of whom 77 473 individuals were exposed to montelukast. Patients were followed up for 12 months. Data were analyzed from June through November 2021. <h3>Exposures</h3> New dispensed prescription for leukotriene receptor antagonist montelukast or control medication. <h3>Main Outcomes and Measures</h3> Incident neuropsychiatric diagnoses at 12 months identified using<i>International Statistical Classification of Diseases, Tenth Revision, Clinical Modification </i>(<i>ICD-10-CM</i>) codes. <h3>Results</h3> There were 72 490 patients with asthma (44 726 [61.7%] women; mean [SD] age at index prescription, 35 [15] years) and 82 456 patients with allergic rhinitis (54 172 [65.7%] women; mean [SD] age at index prescription, 40 [14] years). In patients exposed to montelukast, the odds ratio [OR] for any incident neuropsychiatric outcome was 1.11 (95% CI, 1.04-1.19) in patients with asthma and 1.07 (95% CI, 1.01-1.14) in patients with allergic rhinitis compared with patients who were unexposed. The highest OR was for anxiety disorders (OR, 1.21; 95% CI, 1.05-1.20) among patients with asthma exposed to montelukast and insomnia (OR, 1.15; 95% CI, 1.05-1.27) among patients with allergic rhinitis exposed to montelukast. <h3>Conclusions and Relevance</h3> This study found that patients with asthma or allergic rhinitis had increased odds of adverse neuropsychiatric outcomes after montelukast initiation. These findings suggest that clinicians should consider monitoring potential adverse mental health symptoms during montelukast treatment, particularly in individuals with a history of mental health or sleep problems.
Error in Abstract Results Section
Journal: JAMA Cardiology (2022)

Sonali R. Gnanenthiran, MBBS, PhD; Nelson Wang, MD, MPhil; Gian Luca Di Tanna, PhD; Abdul Salam, PhD; Ruth Webster, PhD; H. Asita de Silva, DPhil; Rama Guggilla, MBBS, MMed; Stephen Jan, PhD; Pallab K. Maulik, PhD; Nitish Naik, MD; Vanessa Selak, PhD; Simon Thom, MD; Dorairaj Prabhakaran, MD; Aletta E. Schutte, PhD; Anushka Patel, PhD; Anthony Rodgers, PhD; TRIUMPH Study Group; Keshinie Samarasekara; Chiranthi Kongala Liyanage; Verni Sopan; Wasantha Kumara; Hansika Pathirana; Lumbini Perera; Manisha Somasiri; Aruna Wijesinghe; Jayamini Jayantha; Sonali Liyanagamage; Muditha de Silva; Chandika Jayawardena; Dilini Karunarathna; Mitrakrishnan Rayno Navinan; Zumra Shukri; Charitha Herath; Nadeeja Seneviratne; Amila Isurangana; Zulaiha Liyakath; Thamal Dasitha; Gerald Rajakulenthiran; Aaisha Azam; Manori Jayawardena; Vinodhan Sunderalingam; Milinda Withana; Anushiya Annaraja; Keshini Soza; Dulani Dasanayake; Dhanushka de Silva; Shakoor Niyasdeen; Uthpala Chandradeva; Safiya Fathima; Aruna Jayawardana; Ranasinghe Chathurika; Manik de Mel; Tharini Mendis; Saumya Withanage; Kandula Pieris; Gayathri Fernando; Chamila Mettanda; Eshani de Silva ; Imali Wijerathna; Jeevaraj Thanushanthan; Devaki Dharmawardena; Shehan Gnanapragasam; Shalomi Weerawardena; Matheesha Suduwelikandage; Ingrid de Silva; Sachini Wathsala; Ruchiranga Ekanayaka; Anuradha Dahanayaka; Vindhya Fernando; Lakmal Jayaweera; Namal Wijesinghe; Murali Dhakshinamurthy; Ullas Arabhavi; Harish Sankarankutty; Mohammed Muddaseer; Sarath Gudivada; Aditi Moitra; Ayesha Tazeen; Karuna Acharya; Prakash Velappan; Ambika Yoganathan; Vipin Jose
Associations of Clinical and Social Risk Factors With Racial Differences in Premature Cardiovascular Disease
Authors: Nilay S. Shah, Hongyan Ning, Lucia C. Petito, Kiarri N. Kershaw, Michael P. Bancks, Jared P. Reis, Jamal S. Rana, Stephen Sidney, David R. Jacobs, Catarina I. Kiefe, Mercedes R. Carnethon, Donald M. Lloyd-Jones, Norrina B. Allen, Sadiya S. Khan
Journal: Circulation (2022)

Background: Racial differences in cardiovascular disease (CVD) are likely related to differences in clinical and social factors. The relative contributions of these factors to Black-White differences in premature CVD have not been investigated. Methods: In Black and White adults aged 18 to 30 years at baseline in the CARDIA study (Coronary Artery Risk Development in Young Adults), the associations of clinical, lifestyle, depression, socioeconomic, and neighborhood factors across young adulthood with racial differences in incident premature CVD were evaluated in sex-stratified, multivariable-adjusted Cox proportional hazards models using multiply imputed data assuming missing at random. Percent reduction in the β estimate (log-hazard ratio [HR]) for race quantified the contribution of each factor group to racial differences in incident CVD. Results: Among 2785 Black and 2327 White participants followed for a median 33.9 years (25th–75th percentile, 33.7–34.0), Black (versus White) adults had a higher risk of incident premature CVD (Black women: HR, 2.44 [95% CI, 1.71–3.49], Black men: HR, 1.59 [1.20–2.10] adjusted for age and center). Racial differences were not statistically significant after full adjustment (Black women: HR, 0.91 [0.55–1.52], Black men: HR 1.02 [0.70–1.49]). In women, the largest magnitude percent reduction in the β estimate for race occurred with adjustment for clinical (87%), neighborhood (32%), and socioeconomic (23%) factors. In men, the largest magnitude percent reduction in the β estimate for race occurred with an adjustment for clinical (64%), socioeconomic (50%), and lifestyle (34%) factors. Conclusions: In CARDIA, the significantly higher risk for premature CVD in Black versus White adults was statistically explained by adjustment for antecedent multilevel factors. The largest contributions to racial differences were from clinical and neighborhood factors in women, and clinical and socioeconomic factors in men.
Perceptions of COVID-19 Vaccine Incentives Among Adolescents and Young Adults
Authors: Caroline M. Hogan, Marika E. Waselewski, Parker Szachta, Clara Wolff, Xochitl Amaro, Tammy Chang
Journal: JAMA Network Open (2022)

<h3>Importance</h3> Vaccine incentives have been used across the US to encourage COVID-19 vaccine uptake and include programs targeted to adolescents and young adults. However, little is known about youths’ views regarding these initiatives. <h3>Objective</h3> To assess experiences and perceptions of COVID-19 vaccine incentives in a nationwide sample of US youth. <h3>Design, Setting, and Participants</h3> A qualitative survey study was conducted using the MyVoice text message-based polling platform from October 22 to October 29, 2021. Participants were US adolescents and young adults aged 14 to 24 years, who were sent 5 open-ended questions to assess their experiences and perceptions of COVID-19 vaccine incentives. Qualitative responses were analyzed thematically. Descriptive statistical analysis was performed in January 2022. <h3>Main Outcomes and Measures</h3> Experiences, perceptions, and opinions related to COVID-19 vaccine incentives as measured by survey response. <h3>Results</h3> A total of 1125 of 1206 youth (93%) responded to the survey and had a mean (SD) age of 20 (2) years, 664 (59%) identified as male, and 769 (68%) identified as non-Hispanic White. Of respondents, 871 (79%) reported having heard of vaccine incentives, and 892 (82%) believed they were a good idea or had positive attributes. Notably, 305 youth (28%) expressed concerns about vaccine incentives, citing uncertainty about their effectiveness (86 [28%]), their ethical use (63 [21%]), the impact on vaccine motivations (51 [17%]), and confidence (39 [13%]), and lack of fairness (35 [11%]). Only 73 youth (7%) reported that an incentive influenced their decision to get a COVID-19 vaccine. When asked what they thought would motivate others to get a COVID-19 vaccine, youth with an opinion (536 of 1032 [52%]) most commonly reported incentives (112 [21%]) and additional COVID-19 vaccine testing, safety, or regulation (115 [21%]). <h3>Conclusions and Relevance</h3> COVID-19 vaccine incentives are well known to youth but not a significant self-reported motivator for vaccination. Although generally viewed favorably, more than a quarter of youth expressed concerns regarding vaccine incentives, including but not limited to their ethics, effectiveness, fairness, and impacts on vaccine motivation and confidence. Policymakers considering targeted use of COVID-19 vaccine incentives should weigh youths’ perspectives on these initiatives alongside objective effectiveness and cost-effectiveness data.
Abstract 3162: Macrophage-derived C/EBPb regulates adult mammary gland homeostasis
Authors: Michelle D. Rojo, Caitlin M. Burke, Alexa M. Dow, Kathryn L. Schwertfeger, Heather L. Machado
Journal: Cancer Research (2022)

Abstract Throughout mammary gland development, there are distinct stages that are “hot spots” of breast cancer risk. During these critical windows, tissue resident macrophages function to maintain the homeostatic balance within the stromal microenvironment and the ductal epithelium, and alterations in these interactions disrupt tissue homeostasis and impact breast cancer risk. However, the signaling and mechanisms by which macrophages regulate mammary gland homeostasis are poorly understood. Our recent studies (and others) have identified transcriptional profiles of distinct tissue resident macrophage subpopulations in the mammary gland. We found that Cebpb, a transcription factor important for myeloid cell differentiation and mammary gland development, is highly expressed in Cx3cr1+ ductal macrophages and localizes to macrophages in close contact with the epithelial ducts. Genetic ablation of C/EBPβ in CSF1R-expressing macrophages results in deficient alveolar budding during diestrus, while branching morphogenesis was normal. Interestingly, this phenotype is also seen in macrophage null models and suggests that C/EBPβ in macrophages plays a crucial role in signaling to the mammary epithelium. Analysis of serum hormone levels show that circulating estrogen and progesterone levels are not changed in CebpbΔMφ mice, however, the number of progesterone receptor (PR)-expressing cells are significantly increased in the ductal epithelium, suggesting altered local progesterone signaling. Further examination of the mammary epithelium shows alterations in a number of Wnt family members, including Wnt1, Wnt2b, Wnt3a and Axin2, indicative of decreased canonical Wnt signaling. Importantly, canonical Wnt signaling has been shown to be critical for regulating mammary stem cell expansion during diestrous budding. Analysis of the C/EBPβ-null macrophages show decreased expression of TGFβ, which is known to signal to basal epithelial stem cells to induce Wnt expression. Finally, other signals, such as Notch 2, which have important roles in the mammary gland development are altered. Ongoing studies are aimed at delineating how macrophage-derived C/EBPβ facilitates mammary stem cell function during the estrous cycle in a progesterone-independent manner. The results of these studies will have critical implications for understanding how the signaling between macrophages and the ductal epithelium regulate tissue homeostasis and the inherent dysregulations that lead to tumorigenesis. Citation Format: Michelle D. Rojo, Caitlin M. Burke, Alexa M. Dow, Kathryn L. Schwertfeger, Heather L. Machado. Macrophage-derived C/EBPb regulates adult mammary gland homeostasis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 3162.
Abstract 6098: Analysis of the impact of ZEB1 expression on pathway enrichment and immune cell abundance in prostate cancer
Authors: Luiz Paulo Chaves, André Luiz Caliari, William Lautert-Dutra, Francisco Cesar Souza Silva, Camila Morais Melo, Fabiano Pinto Saggioro, Rodolfo Borges dos Reis, Jeremy Andrew Squire
Journal: Cancer Research (2022)

Abstract Prostate cancer (PCa) reactivates a latent embryonic program called epithelial-mesenchymal transition during disease progression. The mesenchymal phenotype contributes to invasion, metastasis and therapy response variation. In this study, we characterize the downstream effects of ZEB1 expression based on cohort dichotomization of quartiles of expression comparing the 25% of tumors with high ZEB1 expression to the 75% of tumors with lower ZEB1 expression. Differential gene expression (DGE), gene set enrichment analysis (GSEA) and immune cell abundance prediction were accessed using PCa expression data from TCGA (n=488). ZEB1 high status based on gene expression was stratified based on ZEB1 expression values higher than the 3rd expression quartile value (n=122). Contingency analysis showed that PTEN loss is more frequent in the ZEB1 high group (Chi-square, p=0.0005) which supports previously presented data from our group that showed an inverse correlation between ZEB1 and PTEN protein expression but showed no difference between the groups regarding presence of the TMPRSS2-ERG fusion. DGE showed that more than 13,000 genes are differentially expressed in the ZEB1 high group while GSEA showed that signaling pathways such as HALLMARK TGF BETA, HALLMARK IL2 STAT5, HALLMARK INFLAMMATORY RESPONSE and HALLMARK NOTCH were upregulated in the ZEB1 high group compared to the low group. Yet inflammatory response related pathways were observed enriched in the ZEB1 high group, CIBERSORT analysis showed that effector immune cells such as CD8+ T cells and T helper cells (Holm-Sidak, p=000003 and p=0.000613, respectively) were enriched in the ZEB1 low group in comparison to the ZEB1 high group, which supports previous studies that suggest that ZEB1 cooperates with PTEN loss and TMPRSS2-ERG fusion to promote an immune evasive phenotype in PCa. Collectively, these findings demonstrate that gene expression changes associated with increased ZEB1 expression may involve clinically relevant pathways such as modulation of the tumor immune microenvironment and NOTCH-dependent tumor progression. Citation Format: Luiz Paulo Chaves, André Luiz Caliari, William Lautert-Dutra, Francisco Cesar Souza Silva, Camila Morais Melo, Fabiano Pinto Saggioro, Rodolfo Borges dos Reis, Jeremy Andrew Squire. Analysis of the impact of ZEB1 expression on pathway enrichment and immune cell abundance in prostate cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 6098.
Abstract 1338: Humanized mouse model for in vivo evaluation of bispecific antibody efficacy
Authors: Li-Chin Yao, James G. Keck, Danying cai
Journal: Cancer Research (2022)

Abstract Bispecific antibodies have shown several promising advantages over monoclonal antibodies and are emerging as one of growing cancer immunotherapies. Preclinical in vivo models to assess efficacy associated with immune cell engagement are needed. Here we evaluated an EGFR bispecific T cell engager (EGFRXCD3 BiTE) using xenograft models in humanized NSG™ (NOD.Cg-Prkdcscid Il2rgtm1Wjl/SzJ) mice that have been engrafted with human CD34+ HSC and have human T cells in circulation. Three EGFR+ tumor models were used in this report including LG1202 lung PDX and two triple negative breast cancer cell lines MDA-MB-231 with a high EGFR expression level and MDA-MB-453 with a low EGFR expression. Interestingly we found that all three models were resistant to EGFR monoclonal antibody drug cetuximab despite the expression of EGFR but responded to EGFRXCD3 BiTE. BiTE-induced T cell activation was evident through the analysis of tumor infiltrated lymphocytes by flow cytometry at the end of the study. BiTE treatment for 3 weeks effectively reduced the LG1202 tumor growth whereas the effect of cetuximab on the tumor growth was minimal. In the BiTE-treated group, CD3+ T cell percentage increased as compared to the vehicle group, and both CD4+ and CD8+ T cell subsets showed an increased frequency of CD69+ cells. We also observed elevated levels of human cytokines IFN-γ, IL-6, IL-2, and IL-10 in circulation 4 h after animals received the first BiTE dose. We evaluated the dose response of BiTE treatments on MDA-MB-231 model with a high EGFR expression. Low dose BiTE reduced tumor growth whereas high dose BiTE effectively prevented or even regressed some tumor growth. Flow analysis showed that tumor CD3+ T cell frequency remained similar to the vehicle group but CD8+ T frequency increased after high dose BiTE. High CD69+CD8+ T cell frequency was found in the vehicle group and the percentage further increased after high dose BiTE. For the low EGFR-expressing MDA-MB-453 model, BiTE treatment for 4 weeks also effectively reduced the tumor growth. In comparison, while cetuximab treatment decreased EGFR expression on tumor cells, it did not reduce the tumor growth. Flow analysis showed that BiTE-treated group had increased T cell infiltration into the tumors when compared to the PBS and cetuximab groups. The frequency and cell number of CD25+ and CD69+ CD4+ T and CD8+ T cells in the tumor increased after BiTE treatment. Together, these data support our humanized mouse model to be used to validate T-cell dependent bispecific antibody efficacy. Citation Format: Li-Chin Yao, James G. Keck, Danying cai. Humanized mouse model for in vivo evaluation of bispecific antibody efficacy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 1338.